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© A. Ciuntu, V. Gavriluța, J. Bernic, A-M. Balanuța, A. Gruzinschi



”Nicolae Testemiţanu” State University of Medicine and Pharmacy, Department of Pediatrics,
IMSP Mother and Child Institute


Key words: hemolitic uremic syndrome, thrombocytopenia, acute kidney injury, children, Shiga toxin, Escherichia coli.
Hemolytic-uremic syndrome (HUS) is one of the most common etiologies for acute kidney injury (AKI) and an important
cause of acquired chronic kidney disease (CKD) in children. It mainly affects infants and small children, though older
children and adults may also suffer. A retrospective study was conducted between 2008-2019 in Mother and Child Institute
in Chisinau. The aim of this study was to determine the demographic and clinical characteristics of HUS in children.




Ключевые слова: гемолитико-уремический синдром, тромбоцитопения, острая почечная недостаточность,

дети, диарея, шига токсин, кишечная палочка.
Гемолитико-уремический синдром (ГУС) является одной из ведущих причин развития острой почечной
недостаточности (ОПН) у детей. ГУС считается заболеванием преимущественно детей грудного и младшего
возраста, однако заболеть им могут и дети старшего возраста, и взрослые. Ретроспективное исследование
было проведено в период между 2008-2019 гг. в Институте матери и ребенка в Кишиневе. Целью данного
исследования было определение демографических и клинических характеристик ГУС у детей.




Cuvinte-cheie: sindrom hemolitic uremic, trombocitopenie, leziune renală acută, copii, diaree, Shiga toxina,
Escherichia coli.
Sindromul hemolitic uremic (SHU) este o afecțiune severă, considerată una dintre cele mai frecvente cauze ale
insuficienței renale acute și o cauză importantă a bolii cronice renale (BCR) la copiii mici. SHU se poate instala la orice
vârstă, dar se manifestă mai des la copii cu vârsta sub 5 ani. Această lucrare constituie un studiu retrospectiv realizat în
Clinica de Nefrologie a Institutului Mamei și Copilului, în perioada 2008-2019. Scopul studiului a fost de a determina
caracteristicile demografice și clinice ale SHU la copii.

Introduction. existing conditions such as human immunodeficiency

Hemolytic uremic syndrome (HUS) is a thrombotic virus (HIV) infection, transplantation (bone marrow
microangiopathy characterized with the triad of and solid organ), malignancy, autoimmune diseases,
microangiopathy hemolytic anemia, thrombocytopenia drugs. At the same time current knowledge indicates
and acute renal impairment [1]. that across the world, the majority of HUS are
Recent findings discribe that due to the different associated with gastrointestinal infection with Shiga
etiologies, modes of pathogenesis and clinical toxin-producing enterohaemorrhagic Escherichia coli
presentations, HUS might be associated with disorders (EHEC) strains[2,3].
of complement, which may be hereditary and/or HUS is a life-threatening illness which occurs primarily
autoimmune, cobalamin C deficiency, or with other co- in children younger than 5 years of age. Is a leading cause


of acute kidney injury (AKI) and chronic kidney disease The 11 patients (9 girls and 2 boys) were recorded with
(CKD) in children[3,7]. a mean age at diagnosis of 4,58±1,1 years, with the limits
HUS was first described by Swiss pediatric hematologist between 7 months and 10 years.
Conrad von Gasser, who reported five cases of HUS, The distribution of children by gender shows a prevalence
those children died in the acute phase in 1955[2]. of SHU syndrome among girls up to 81,81% of cases. The
Several years later in 1983 Karmali et al. establish a link distribution by region of provinience reflects a high rate
between an increased Stx activity in fecal filtrates and among urban children about 72% compared to the rural
sporadic post-diarrheal HUS[4]. area. In 90% of cases HUS in children occurred during
The annual incidence has been reported to be 0,7–8 cases the spring-summer season. Clinical profile of the most
/ 100,000 population, with seasonal and geographical of the patients was dominated in a prodromal phase by
variability. The disease can be encountered at any age diarrhea and abdominal pain.
but more frequently occurs in children younger than 6 Bloody diarrhea was present in 81,81% of children
years[2,8]. The highest incidence HUS is reported in the with HUS. On admission to the hospital, oliguria
late summer and autumn months but may occur both was present only in 2 children (18%) as a dominant
sporadically and in localized epidemics. symptom, other 9 children developed oligoanuria at
In children ocurence of tipical is up to 85-90% of total some point during hospitalization. In 2 children, the
cases, atipical HUS is roughly one-tenth of the incidence. initial sign was excessive pallor of the skin, jaundice,
The frequency of secondary HUS due to the coexistence and the chromatic change of the urine into brown.
of a disease or condition is not yet documented[4,5]. Clinical presentation with vomiting( single or repeated)
In Europe, SHU is caused in about 90% by the Shiga toxin was recorded in 54,5% of cases, dehydration and fever
produced by Escherichia coli (STEC).The most common in 81,81% of cases.
serotype responsible of the disease is E.coli O157:H7 The average time from the onset of the prodromal phase
followed by O26:H11/H [1,4,6,7]. to the diagnosis was 7 days. 31±2,0 constitutes the mean
Other enterohemorrhagic serotypes encountered in value of hospital days, the minimum number of days
afected children are O111/H8/H (11%), O145: 28/H- constituted 11, and the maximum number 60.
(11%) și O103/H2/H- (6%),meanwhile O55, O27, O118 Table 1 and 2 contains sugestive laboratory values. The
and O120 strains represent less than 1% of the total cases. mean haemoglobin value at admission was 63 ± 3,37/
In the epidemiological structure, the mortality rate of dL. Serum LDH was increase- 3033±44 U/L, it can be
HUS is up to 7%; and a significant percentage about 12- interpreted as a marker of hemolysis. The average number
30% of cases are affected by long-term sequelae, such as of platelets at admission was 28,89±6,5. One patient,
kidney or neurological injury[1,4]. had single platelets, clinically manifested by cutaneous
hemorrhagic syndrome.
Objective. Conclusive signs of severe impairment of glomerular
To provide an update on the understanding clinical and function were translated by the development of the
therapeutic concepts regarding SHU through the prism syndrome of nitrogen retention, the mean value of serum
of this study. creatinine registering 368,56±64,2 μmol/l. At the same
time 2 of the patients reached maximum serum creatinine
Methods. values of 680 μmol/l and 530 μmol/l respectively. An
We conducted a retrospective study collecting data from increased marked value was also found in the biochemical
medical records of 11 children with HUS who have been evaluation of blood urea with an average value of 37,1±7
followed at the Pediatric Nephrology unit in Mother mmol/l. The mean value of eGFR reached 14,3±1,4 ml/
and Child Institute in Chisinau, between 2008 and 2019. min/1,73 m2.
Criteria for diagnosis of HUS were the presence of the We recorded extrarenal features in about 90,9% of the
clinical triad of micro-angiopathic hemolytic anaemia, cases. The gastrointestinal manifestations were in the
thrombocytopenia and AKI. form of hemorrhagic colitis, pancreatitis with impaired
All relevant data were recorded. The following exocrine function, toxic hepatitis, acute appendicitis.
aspects were evaluated: demographic data (age, sex, Cardiac complications were reported in 5 patients
environment of origin), history, symptoms and time (45,45%) they developed high blood pressure, and in
of onset. Also we studied laboratory data including one patient, echocardiographic and clinical evaluation
full blood count, biochemical data and results of other showed tricuspid valve II insufficiency, moderate pulmo-
instrumental investigation. We used the Schwartz nary hypertension 40 mm/Hg and cardiac insufficien-
Equation to estimate GFR. cy CF II NYHA. Pulmonary edema was diagnosed in 2
patients during hospitalization. Neurological involvment
Results. included convulsions (2 patients), encephalopathy (3 pa-
In the study group, the therapeutic indications were based tients), cerebral edema (2 patients). In 54,54% of patients
on clinical, imaging, laboratory criteria which evaluated developed dyselectronemia manifested by hyperkalae-
over time allowed to appreciate the systemic changes. mia, hyponatremia or hypocalcemia.


Table 1. Complete blood count in prodromal phase Discussion.

in children with HUS Acute renal injury is characterized by progression to
Hb g/dl
oligoanuria and severe electrolyte imbalances, which
Mean±SD 63±3,37 require renal replacement therapy in 50% -70% of
Median 59 patients. Acute renal injury in STEC-HUS patients ranges
Erythrocytes (x 10 6/mm3) from asymptomatic urinary sediment abnormalities to
Mean± SD 2,23±0,11 severe renal failure and end-stage renal disease [9].
Median 2,33
Leukocytes (x 10 9/mm3) The clinical course of a majority of patients with typical
Mean± SD 8,95±1,63 HUS, usualy result in a full recovery based on clinical
Median 8,3 and laboratory assessments. Nevertheless, a significant
Thrombocytes (x 10 9/mm3) percentage are affected by long-term sequelae[10].
Mean± SD 28,89±6,5 Systemic presentation of HUS varies greatly between
Median 29
patients, depending on the organs affected by the
Table 2. Serum biochemistry analysis in children with HUS thrombotic microangiopathy process. Complications
Creatinine μmol/l usualy include the central nervous system and the
Mean± SD 368,5±64 gastrointestinal, cardiac and musculoskeletal systems[11].
Median 368 Several studies reveled that children with typical HUS and
Ureea mmol/l central nervous system, gastrointestinal or myocardial
Meaân± SD 37,1±7
Median 34 involvement have a higher morbidity and mortality rate
Protein total g/l during the acute phase of HUS[11,12].
Mean± SD 58,87±3,4 Acording to literature data neurological impairment is
Median 58
one of the most severe complications of STEC-SHU, and
Mean± SD 93±22 is responsible for most patient deaths, thus contributing
Median 75 to the increased morbidity of the disease. Neurological
AST (U/L) manifestations are related to hypertension, electrolytic
Mean± SD 85,1±18
Median 64 disorders (hyponatremia) and microtombosis in the
LDH (U/L) central nervous system[13].
Mean± SD 3033±44 Nathanson et al. revelead neurologic involvement is
Median 2756 associated with a severe renal disease but does not lead
Na μmol/l
Mean± SD 130,7±2,8 systematically to death or severe disability[14].
Median 132 A systematic review of scientific articles mention that
Kμmol/l the diarrhea and associated gastrointestinal complaints
Mean± SD 5,64±0,1 in the prodromal phase of Stx-HUS may mimic those
Median 5,67
Ca μmol/l of ulcerative colitis, other enteric infections, and
Mean± SD 1,82±0,07 appendicitis this moment might delay the time of the
Median 1,88 diagnostic[15]. Biological pancreatitis, as well as elevated
liver enzymes, occur in 20% of STEC-HUS patients but
Hemodialysis therapy was initiated in 54,54% of patients
do not commonly result in organ failure[16].
diagnosed with HUS. Hemodialysis was performed
Cardiac involvement are potentially life-threatening
based on the following data - increased urea> 100 mg/l,
complication. We recorded poor cardiac complications
creatinine> 5 mg/l, endogenic creatinine clearance <7-
the same rate is reported in the literature. Data on it’s
10 ml/min/1,73 m2, metabolic acidosis, hyperkalaemia,
incidence in children with HUS are limited and reported
mainly as isolated case reports. Although clinical
The maximum number of hemodialysis sessions were 11.
manifestations of myocardial involvement in HUS
After 11 days of hemodialysis, the diuresis began to recover,
are diverse, and they include myocardial dysfunction
and serum creatinine and ureea began to decline. Despite
(poor peripheral perfusion and pulmonary edema),
the polyuria in the initial phase of renal function recovery,
myocarditis, cardiac tamponade, dilated cardiomyopathy
due to the retention of still significant fluids, continuous
and even myocardial infarction[15,16].
intravenous infusion with furosemide was continued.
A study from Romania conducted throught out
Endovenous infusions with 0,9% NaCl soil were per-
32 children described in 21, 65,6% of case, cardiac
formed as a symptomatic therapeutic strategy. Substitu-
complication which were diagnosed at admission and
tion therapy in severe anemia was performed with red
during hospitalization, when left ventricular hypertrophy,
blood cell and freshly frozen plasma.
diastolic dysfunction and pericarditis were the main
One patient with HUS died developing Multiple Organ
echocardiographic findings. However, these injuries were
Dysfunction Syndrome, the oliguria settled in 4 days after
reversible, in their majority, and following a 6-12 months
the appearance of frequent diarrhea, vomiting. HUS in
follow-up, residual left ventricular hypertrophy was
this case was complicated with pleural effusion, ascites,
present in only 3 patients[17].
hypertension, pancreatitis.


Current researches describe controversial data about 7. Takashi Igarashi, Shuichi Ito, Mayumi Sako.
clinical outcome in children with HUS.The illness Guidelines for the management and investigation
and death rate of patients with diarrhea-associated of hemolytic uremic syndrome. Clinical and
HUS remained high. The study of Balgragean M. et al. Experimental Nephrology.2014;DOI 10.1007/s10157-
revealed death of three patients (9,4%) of cases, during 014-0995-9.
hospitalization[17]. Similar data we obtain in our study 8. Goodship TH., Cook HT .et al. Atypical hemolytic
also a 9% mortality, one child died during the acute phase uremic syndrome and C3 glomerulopathy: conclusions
of the disease. HUS in children remains an important from a “Kidney Disease: Improving Global Outcomes”
health concern. Our study emphasizes that prompt (KDIGO) Controversies Conference. Kidney Int.
recognition is important to prevent significantly poor 2017;91(3):539.
outcomes. 9. Bowen EE., Coward RJ. Advances in our
understanding of the pathogenesis of hemolytic
Conclusions. uremic syndromes. Am J Physiol Renal Physiol. 2018
HUS is a severe condition, being one of the most common Mar 1;314(3):F454-F461.
causes of acute renal failure and an important cause of CKD 10. Braune SA., Wichmann D. et al. Clinical features
in infants under 5 years of age. The syndrome also affects of critically ill patients with Shiga toxin–induced
other organ systems, characterized by hematological, hemolytic uremic syndrome. Crit Care Med.
cardio-circulatory, digestive, hepatic, neurological 2013;41:1702-10.
dysfunctions. Surveillance of children who have sustained 11. Harkins V.J., McAllister D.A. Reynolds B.C. Shiga-
SHU allows the clinical paraclinical monitoring of long- Toxin E. coli Hemolytic Uremic Syndrome: Review of
term sequelae (high blood pressure, proteinuria, etc.) Management and Long-term Outcome. Curr Pediatr
to reduce the risk of developing chronic kidney disease. Rep. 2020; 8: 16-25.
12. Rahman RC., Cobeñas CJ., Drut R., Amoreo OR., et
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